Multiple myeloma is an incurable B cell tumor with limited treatment options. Our goal is to study the ability of the host immune system to resist this tumor in patients. Clonal expansion of transformed plasma cells with nearly all of the known genomic and cytogenetic changes found in myeloma can remain clinically stable for prolonged periods in patients with preneoplastic gammopathy (MGUS). Our preliminary studies suggest that these patients mount a vigorous and specific immune response against tumor cells in the tumor bed, which is not found in myeloma patients. Our hypothesis is that the host immune response plays a key role in controlling the malignant growth of tumor cells in patients, and this response is critically dependent on the context of tumor-dendritic celI-T cell interactions in vivo. MGUS-myeloma is a particularly useful model to study tumor-immune interactions, as it is possible in this tumor to isolate tumor and immune effector and antigen presenting cells directly from the bone marrow tumor bed, without the need for ex vivo culture and enzymatic treatments. Our long-term goal is to learn to harness the host immune response in an attempt to prevent progression of MGUS to myeloma. Our specific aims are 1) to study the nature of host anti-tumor CD4+ and CD8+ T cell response in the blood and tumor bed of patients with myeloma and MGUS; 2) to characterize the nature of antigen-presenting cells in the tumor bed and their interactions with tumor cells in situ; and 3) to study whether specific subpopulations of tumor cells can be specifically targeted to dendritic cells, the body's natural adjuvant. These studies should provide novel information about the interactions between tumor cells and immune system in the context of tumor microenvironment; and suggest novel strategies to boost anti-tumor immunity in patients targeting dendritic cells.